Contents

Medical use

Methoxyflurane has been extensively used since the 1970s in Australia as an emergency analgesic for short-term use, mostly by the
Australian and
New Zealand Defence Forces,[4] and the
Australian ambulance services.[5][6][7] The drug is currently only available from one manufacturer (Medical Developments International, Melbourne, Victoria, Australia). It is self-administered to children and adults using the
Penthrox inhaler, a hand-held inhaler device, known as "the green whistle".[4][5][8][9] A non-
opioid alternative to
morphine, it is also easier to use than
nitrous oxide.[10] As of 2010, methoxyflurane was listed under the
Pharmaceutical Benefits Scheme for the initial management of pain due to acute trauma, as well as for brief painful procedures such as changing of wound dressings or for patient transport.[10] A portable, disposable, single-use inhaler device (the Penthrox inhaler), along with a single 3 milliliter brown glass vial of methoxyflurane is provided in doctor's kits that allows conscious hemodynamically stable patients (including children over the age of 5 years) to self-administer the drug, under supervision.[10]

Each 3 milliliter dose lasts approximately 30 minutes.[11] Pain relief begins after 6–8 breaths and continues for several minutes after stopping inhalation.[12] The maximum recommended dose is 6 milliliters per day or 15 milliliters per week because of the risk of cumulative dose-related nephrotoxicity, and it should not be used on consecutive days.[10] Despite the potential for renal impairment when used at anesthetic doses, no significant adverse effects have been reported in the literature when it is used at the lower doses (up to 6 milliliters) used for producing analgesia and sedation.[5][9][13] Due to the risk of organ (especially renal)
toxicity, methoxyflurane is
contraindicated in patients with pre-existing
kidney disease or
diabetes mellitus, and is not recommended to be administered in conjunction with tetracyclines or other potentially nephrotoxic or
enzyme-inducing drugs.[9]

The carbon–fluorine bond, a component of all organofluorine compounds, is the strongest
chemical bond in organic chemistry.[21] Furthermore, this bond becomes shorter and stronger as more fluorine atoms are added to the same carbon on a given molecule. Because of this,
fluoroalkanes are some of the most
chemically stable organic compounds.

Pharmacokinetics

Methoxyflurane has a very high lipid solubility (oil:gas
partition coefficient of around 950), which gives it very slow
pharmacokinetics (induction and emergence characteristics); this being undesirable for routine application in the clinical setting. Initial studies performed in 1961 revealed that in
unpremedicated healthy individuals, induction of general anesthesia with methoxyflurane-
oxygen alone or with nitrous oxide was difficult or even impossible using the vaporizers available at that time. It was found to be necessary to administer an
intravenous anesthetic agent such as
sodium thiopental to ensure a smooth and rapid induction. It was further found that after thiopental induction, it was necessary to administer nitrous oxide for at least ten minutes before a sufficient amount of methoxyflurane could accumulate in the
bloodstream to ensure an adequate level of anesthesia. This was despite using high flow (liters/minute) of nitrous oxide and oxygen, and with the vaporizers delivering the maximum possible concentration of methoxyflurane.[19]

Similar to its induction pharmacokinetics, methoxyflurane has very slow and somewhat unpredictable emergence characteristics. During initial clinical studies in 1961, the average time to emergence after discontinuation of methoxyflurane was 59 minutes after administration of methoxyflurane for an average duration of 87 minutes. The longest time to emergence was 285 minutes, after 165 minutes of methoxyflurane administration.[19]

Unlike diethyl ether, methoxyflurane is a significant respiratory depressant. In dogs, methoxyflurane causes a
dose-dependent decrease in
respiratory rate and a marked decrease in
respiratory minute volume, with a relatively mild decrease in
tidal volume. In humans, methoxyflurane causes a dose-dependent decrease in tidal volume and minute volume, with respiratory rate relatively constant.[22] The net effect of these changes is profound respiratory depression, as evidenced by
CO2 retention with a concomitant decrease in arterial
pH (this is referred to as a
respiratory acidosis) when anesthetized subjects are allowed to breathe spontaneously for any length of time.[19]

Gastrointestinal effects

In a series of 500 consecutive obstetric
patients, Boisvert and Hudon observed vomiting in 12 (4.8%) patients during or after administration of methoxyflurane anesthesia. These findings compared favorably with those reported for
cyclopropane (42%),
trichloroethylene (28%) and halothane (4.6%).[27] In another study of 645 obstetric patients, Romagnoli and Korman observed 8 cases (1.2%) of
postoperative vomiting, one of whom was
retching before the administration of the anesthetic.[28]

Analgesic effects

Although the high blood solubility of methoxyflurane is often undesirable, this property makes it useful in certain situations—it persists in the
lipid compartment of the body for a long time, providing
sedation and analgesia well into the postoperative period.[18][22] There is substantial data to indicate that methoxyflurane is an effective analgesic and sedative agent at subanesthetic doses.[4][5][6][7][29][30][31][32][33][34][35][36][37] Supervised
self-administration of methoxyflurane in children and adults can briefly lead to deep sedation,[5] and it has been used as a patient controlled analgesic for painful procedures in children in hospital
emergency departments.[8] During
childbirth, administration of methoxyflurane produces significantly better analgesia, less
psychomotor agitation, and only slightly more
somnolence than trichloroethylene.[29]

In 1968, Robert Wexler of Abbott Laboratories developed the Analgizer, a disposable
inhaler that allowed the self-administration of methoxyflurane vapor in air for analgesia.[38] The Analgizer consisted of a
polyethylene cylinder 5 inches long and 1 inch in diameter with a 1 inch long mouthpiece. The device contained a rolled
wick of
polypropylenefelt which held 15
milliliters of methoxyflurane. Because of the simplicity of the Analgizer and the
pharmacological characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level of
conscious analgesia which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15 milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partly
amnesic to the sense of pain; the device could be refilled if necessary.[32] The Analgizer was found to be safe, effective, and simple to administer in obstetric patients during childbirth, as well as for patients with
bone fractures and
joint dislocations,[32] and for dressing changes on
burn patients.[31] When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent
adverse effect on
Apgar scores.[32] All
vital signs remain normal in obstetric patients, newborns, and injured patients.[32] The Analgizer was widely utilized for analgesia and sedation until the early 1970s, in a manner that foreshadowed the patient-controlled analgesia infusion pumps of today.[29][30][33][34] The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the
Penthrox inhaler.[4][5][8][9] Trials of methoxyflurane as an analgesic in emergency medicine are going on in the UK.

Biodegradation and toxicity

The first report of nephrotoxicity appeared in 1964, when Paddock and colleagues reported three cases of acute renal insufficiency, two of whom were found to have calcium
oxalate crystals in the renal tubules at autopsy.[44] In 1966, Crandell and colleagues reported a series in which 17/95 (18%) of patients developed an unusual type of
nephropathy after operations in which methoxyflurane was used as a general anesthetic. This particular type of
renal insufficiency was characterized by
vasopressin-resistant
high-output renal failure (production of large volumes of poorly concentrated urine) with a negative fluid balance, pronounced weight loss, elevation of serum sodium, chloride,
osmolality and blood urea nitrogen. The urine of these patients was of a relatively fixed
specific gravity and an osmolality very similar to that of the serum. Furthermore, the high urine output persisted a challenge test of fluid deprivation. Most cases resolved within 2–3 weeks, but evidence of renal dysfunction persisted for more than one year in 3 of these 17 cases (18%), and more than two years in one case (6%).[45]

Reports of severe and even fatal hepatotoxicity related to the use of methoxyflurane began to appear in 1966.[46][47][48][49][50][51][52][53][54] These reports prompted anesthesiologists to subject this agent to intense and systematic scrutiny. A study published in 1973 by Cousins and Mazze demonstrated that compared with halothane, methoxyflurane produces dose-dependent and deleterious abnormalities in
renal function. The authors showed that
subclinical nephrotoxicity occurred following methoxyflurane at minimum alveolar concentration (MAC) for 2.5 to 3 hours (2.5 to 3 MAC hours), while overt toxicity was present in all patients at dosages greater than five MAC hours.[55] This landmark study provided a model that would be used for the assessment of the nephrotoxicity of volatile anesthetics for the next two decades.[56]

The biodegradation of methoxyflurane begins immediately after the onset of exposure. The
kidney and
liver toxicity observed after anesthetic doses is attributable to one or more
metabolites produced by O-
demethylation of methoxyflurane. Significant products of this
catabolic process include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride.[57] Methoxyflurane nephrotoxicity is dose dependent[45][58][59] and irreversible, resulting from O-demethylation of methoxyflurane to fluoride and DCAA.[10] This effect is so predictable and reproducible that methoxyflurane now serves as a pharmacologic model of fluoride-related nephrotoxicity, one with which newer drugs are compared.[56] It is not entirely clear whether the fluoride itself is toxic—it may simply be a
surrogate measure for some other
toxic metabolite.[60] The concurrent formation of inorganic fluoride and DCAA is unique to methoxyflurane
biotransformation compared with other volatile anesthetics, and this combination is more toxic than fluoride alone. This may explain why fluoride formation from methoxyflurane is associated with nephrotoxicity, while fluoride formation from other volatile anesthetics (such as
enflurane and
sevoflurane) is not.[61] Furthermore, the concurrent use of
tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity.[62]

Based on the findings of these and other studies in the early 1970s, the current consensus is that the use of methoxyflurane should be restricted only to healthy individuals, in situations where it offers specific advantages and even then, only at dosages less than 2.5 MAC hours.[55][57] Partly because of these warnings, but also because of the development of newer volatile anesthetics such as enflurane,
isoflurane,
desflurane and sevoflurane, the clinical use of methoxyflurane as a general anesthetic in humans was largely abandoned in the mid-1970s.

Significant obstacles had to be overcome in the handling of both fluorine and UF6. Before the
K-25 gaseous diffusion
plant could be built, it was first necessary to develop
non-reactivechemical compounds that could be used as
coatings, lubricants and gaskets for the surfaces which would come into contact with the UF6 gas (a highly reactive and
corrosive substance). William T. Miller,[69] professor of
organic chemistry at
Cornell University, was co-opted to develop such materials, because of his expertise in organofluorine chemistry. Miller and his team developed several novel non-reactive
chlorofluorocarbonpolymers that were used in this application.

Charles Suckling synthesized
halothane in 1951. Halothane was the first organofluorine anesthetic agent to be introduced into clinical practice in 1956.[70] Miller and his team continued to develop organofluorine chemistry after the end of World War II and methoxyflurane was synthesized in 1948.[1]